New-onset focal epilepsy in adults: Antiepileptic drug treatment
Focal epilepsy, non-syndromic, is by far the most prevalent epilepsy in adults. Antiepileptic drug (AED) prescription in patients with new-onset focal epilepsy is often challenging. The factors that determine AED of choice depends both on the patient-specific and AED-specific variables. Monotherapy should the initial strategy. Failure to monotherapy can be due to lack of efficacy, severe adverse events, or a hypersensitivity reaction. In such patients, the next strategy should be alternate monotherapy trials. In patients who fail up to three monotherapy trials, duotherapy with drugs having different primary mechanisms of action should be the next step. Multiple duotherapy should be tried before considering adding polytherapy. In spite of such pragmatic strategies, about 25% of patients may never become seizure free for any complete year throughout follow-up. Patients in this group should be evaluated for non-pharmacological treatment options, particularly epilepsy surgery.
Keywords: Antiepileptic drugs, duotherapy, focal epilepsy, monotherapy, rational polytherapy
Epilepsy is a common chronic brain disease, affecting about 60 million people worldwide with 34–76 per 100,000 new cases being added annually. Circumstantial evidence, mostly from resource poor countries suggests that about two-thirds of newly diagnosed cases of epilepsy achieve remission with or without antiepileptic drug (AED) treatment and about a third persist to have seizures. Epilepsy is a potentially treatable condition and with the currently available AEDs, about 70 – 80% of patients with newly diagnosed epilepsy will enter seizure remission while on drug treatment., About 60% of patients remain seizure free even after AEDs have been withdrawn. Focal epilepsy is by far the most prevalent epilepsy in adults. Recent International League Against Epilepsy (ILAE) Commission on Classification and Terminology classifies the aetiology of epilepsies into genetic (electro-clinical syndromes), structural/metabolic, and unknown causes. Epilepsies due to the latter two aetiologies are considered under non-syndromic epilepsies. This review discusses AED treatment of new-onset, non-syndromic (structural/metabolic and unknown cause) focal epilepsy in adults.
AEDs: When to start
Based upon the new definition of epilepsy by the Task Force of ILAE, AED treatment should be started in patients with (1) at least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Risk factors for enduring recurrence of seizures include: prior brain insult (Level A); an EEG with epileptiform abnormalities (Level A); significant brain-imaging abnormality (Level B); and the occurrence of a nocturnal seizure (Level B). Other important considerations before the initiation of AED in patients with newly diagnosed epilepsy should be the type and natural course of epilepsy and epilepsy syndrome.
AEDs: What to start
The AED selected in an individual patient with new-onset focal epilepsy ideally should fully control the seizures, be well-tolerated with no long-term safety issues particularly teratogenicity, be easy to administer, have no drug interactions, have favourable pharmacokinetics, may not need serum monitoring, and have a low cost. No single AED meets these criteria. The choice of AED depends on multiple factors [Table 1].,
Since the 1980s, several new AEDs with different mechanism(s) of action and safety profile have been introduced, providing more choice for the individual patients with focal epilepsy., Most of the standard and newer AEDs have been shown to have efficacy in the presence of new-onset focal epilepsy in adults in randomized, comparative, long-term monotherapy trials [Table 2] and [Table 3]. However, most of these trials failed to identify major differences in seizure freedom rates among the drugs being compared.
The SANAD trial of AED monotherapy in adults with focal epilepsy showed similar efficacy of carbamazepine, lamotrigine, and oxcarbazepine, but a lower comparative efficacy of gabapentin and. topiramate., In an unblended randomized study, levetiracetam monotherapy was as effective as controlled-release carbamazepine for patients with focal epilepsy. A randomized, double-blind trial comparing levetiracetam and controlled-release carbamazepine in adults with focal seizures, produced equivalent seizure freedom rates. In the phase III randomized, double-blind, parallel-group, non-inferiority trial in adults with focal epilepsy, zonisamide was non-inferior to controlled-release carbamazepine. Updated ILAE evidence review of antiepileptic efficacy and effectiveness as initial monotherapy showed Level A evidence for carbamazepine, phenytoin, levetiracetam, and zonisamide for focal seizures in adults. All the trials discussed above show carbamazepine having similar efficacy as the newer AEDs for focal seizures.
Among the standard AEDs, valproate is less efficacious than carbamazepine in reducing the frequency of dyscognitive seizures (complex partial seizures). The major concerns for phenytoin are its complicated pharmacokinetics and spectrum of adverse effects. Phenobarbital has a broad spectrum of activity. A meta-analysis of randomized trials suggests that few differences exist between phenobarbital and other standard AEDs. Phenobarbital has been shown to be less effective than carbamazepine or phenytoin for focal seizures in mostly newly diagnosed focal epilepsy.
A meta-analysis of the newer AEDs – placebo controlled studies in focal epilepsy, using sustained freedom from seizures as the outcome measure, showed the overall weighted pooled-risk difference in favour of newer AEDs compared with placebo for seizure freedom as being only 6% (94% CI 4 – 6) and the number needed to treat in terms of freedom from seizure was sixteen.,
The preferential use of standard AEDs is recommended as monotherapy in patients with new-onset epilepsy, particularly in resource poor countries, unless there are specific reasons for doing otherwise. Based on the available evidence, the initial monotherapy-of-choice in adult patients with new-onset focal epilepsy is carbamazepine among the standard AEDs, and levetiracetam among the newer AEDs. Other AEDs may be reasonable alternatives if carbamazepine or levetiracetam are unsuitable, not tolerated, or lack efficacy [Table 2] and [Table 3].,,,
AEDs: How to initiate
The gold standard strategy of initial treatment of new-onset focal epilepsy is monotherapy. The advantages of monotherapy include: It permits evaluation of the efficacy and adverse effects of the selected AED; reduces the toxicity; eliminates the risk of pharmacological interaction between AEDs; improves drug adherence; and minimizes the costs. The AED treatment is generally started with a low dose, which is then increased with time to the optimal dose. A gradual titration can improve central nervous system tolerability, reduce the risk of idiosyncratic adverse events, or both. Most patients achieving seizure freedom on the first AED do so at a lower dose.
Failure of initial monotherapy: Substitution versus add-on
In a clinic-based study, about 62% of patients with new-onset epilepsy achieved seizure remission on either initial or alternate monotherapy. Failure to the first appropriate AED may be due to the lack of efficacy or the occurrence of adverse events, including an idiosyncratic reaction., Options in such patients are two: An alternate monotherapy (substitution) or a combination therapy (add-on). However, the evidence for either of the options is lacking. The arguments for the alternate appropriate monotherapy include: It permits evaluation of the efficacy and adverse effects of the selected AED; reduces the toxicity associated with combination therapy; eliminates the risk of pharmacological interaction between AEDs; and, improves drug adherence. The argument against add-on therapy in patients who fail to the first appropriate AED has been its propensity to cause greater toxicity without substantial improvement in outcome.
The earlier randomized trials with a small sample size , and the Italian prospective observational study  did not provide clear evidence for the strategy that should be preferred. The Italian study suggests that the preferred use of alternate monotherapy when the initial monotherapy fails, does not necessarily lead to a better outcome, in terms of seizure recurrence and adverse treatment effects. An open, cluster-randomized, prospective, controlled trial in patients with persistent focal seizures, despite treatment with one AED, compared efficacy of alternate monotherapy versus an early add-on treatment. The efficacy and incidence of adverse events were similar in both the groups. In a prospective observational study of patients in whom the first AED was unsuccessful, there was no significant difference in seizure-free rates and the incidence of intolerable side effects between the substitution group and the add-on group.
In the absence of a high level of evidence in favor of either alternative monotherapy or add-on therapy, one of the suggested options is to evaluate the combination therapy and then attempt to withdraw the first drug in the case of success (transitional combination therapy). Such an approach may prevent the substitution of a partially efficacious drug by a non-efficacious drug. The data from the clinic-based study, of the 1,098 patients with newly diagnosed epilepsy, suggested that 543 (49.4%) patients were seizure-free with the first appropriate AED used as monotherapy; 136 (12.4%) patients were seizure-free with alternate monotherapy (second to seventh drug regime); and, after three monotherapy trials, the chance of seizure freedom was seen in less than 1% of patients.
After failure of three sequential monotherapy trials, duotherapy may be an option. With the availability of modern non-enzyme inducing drugs, it has become easier to implement and maintain add-on treatment when it is a necessity., In the Western Infirmary, Glasgow clinic-based study, of the 70 patients with newly diagnosed epilepsy who remained seizure free on more than 1 drug, 67 (96%) patients were on duotherapy. Testing of several duotherapy combinations sequentially before trying polytherapy has been suggested., In the Western Infirmary, Glasgow clinic data, of the 2379 seizure-free patients, 486 (20.4%) remained controlled on combination therapy for one or more years: 395 (81.1%) on duotherapy; 85 (17.5%) on three AEDs; and, 6 (1.2%) on four AEDs. Of the 486 seizure-free patients on polytherapy, 309 (63.6%) had focal epilepsy.
Add-on therapy can be a rational combination of AEDs. Conceptually “rational polytherapy” assumes that AED combinations with differing mechanisms of action are more effective than polytherapy with similar mechanisms of action. The availability of non-enzyme inducing AEDs and AEDs with multiple and novel mechanisms of action allows clinicians to practice rational polytherapy. The ideal AED combination should possess additive, supra-additive, or synergistic effects in terms of efficacy with fewer non-serious adverse effects [Table 4]. A rational choice of drug combinations is currently based more on avoidance of pharmacodynamics or pharmacokinetic side effects than on evidence for supra-additive or synergic effects. The proposed guidelines for combining AEDs by Brodie and Sills include: (1) Optimize the dose of baseline AED; (2) add AEDs with multiple mechanisms; (3) avoid combining AEDs with similar modes of action; (4) titrate the new AED slowly and carefully; (5) be prepared to reduce the dose of the original AED; (6) replace less effective drug if response is still poor; (6) try the range of different duotherapies; and, (7) add a third drug if there is still sub-optimal control.
The clinical evidence in support of rational polytherapy is very limited.,,, Data from the observational studies suggest that combining two sodium channel blockers is less effective than combination of drugs with different primary mechanisms of action. Combination of valproate and lamotrigine has the best clinical evidence of synergy. Valproate increases the serum level of lamotrigine through metabolic inhibition. Clinical trials studying the efficacy of lacosamide in patients with focal epilepsy suggest that the combination of lacosamide and levetiracetam has possible additive efficacy., Pooled analysis of three phase II/III clinical trials examining the clinical use of lacosamide in patients with focal epilepsy showed a high 50% responder rate in the subgroup treated with lacosamide and concomitant levetiracetam use. Another clinical study conducted in patients with focal epilepsy showed the highest seizure freedom and 50% responder rate in the subgroup treated with lacosamide and levetiracetam compared to other AEDs. In the Western Infirmary, Glasgow clinic-based data, of the 486 patients (63.6% with focal epilepsy) who remained controlled on combination therapy for one or more years, most were on AEDs with different mechanisms of action. In the absence of evidence-based guidelines on how and when to combine AEDs, the current practice recommendations are largely empirical.
Drug resistant epilepsy
Failure to achieve sustained seizure remission with two trials of adequately dosed AEDs should signal drug-resistant epilepsy. The ILAE Task Force defines drug resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve a sustained seizure-freedom. Seizure freedom is defined as freedom from seizures for a minimum of three times the longest pre-intervention inter-seizure interval (determined from seizures occurring within the past 12 months) or 12 months, whichever is longer. However, there is considerable heterogeneity in the long-term seizure patterns in people who do not enter long-term remission in the early years after diagnosis. Several studies have shown that some of these patients achieve seizure-freedom after several years of continuous activity and after multiple trials of more than two AEDs.,,, In an analysis of outcome of seizures over time in the study by Brodie et al., 25% of patients never become seizure-free for any complete year throughout follow-up. Non-pharmacological treatment options, particularly epilepsy surgery, should be explored in this group of patients with drug resistant focal epilepsy.
Focal epilepsy is by far the most prevalent epilepsy in adults. The aetiology of focal epilepsy include genetic, structural/metabolic, and unknown causes. The natural course of genetic focal epilepsy is predictable and most often these focal epilepsies respond to the appropriate monotherapy. AED prescription in patients with new-onset focal epilepsy is often challenging. Monotherapy should the initial strategy. Failure to monotherapy can be due to lack of efficacy, severe adverse events, or hypersensitivity reaction. In such patients, the next strategy should be alternate monotherapy trials. In patients who fail to three monotherapy trials, duotherapy with drugs having different primary mechanisms of action should be tried. Multiple duotherapy should be tried before considering adding a third or fourth drug. In spite such pragmatic strategies, about 25% of patients may never become seizure free for any complete year throughout follow-up. Patients in this group should be evaluated for non-pharmacological treatment options, particularly epilepsy surgery.
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[Table 1], [Table 2], [Table 3], [Table 4]